The efficacy of stereotactic body radiation therapy on huge hepatocellular carcinoma unsuitable for other local modalities

Hepatocellular carcinoma (HCC) is one of the most common malignancy worldwide, and the leading cause of cancer death in South and East Asia. In small HCC, hepatic resection and other nonsurgical treatment modalities have contributed to good survival [1, 2]. However, treatment for huge HCC (≧ 10 cm in diameter) remain a challenge. At present, hepatic resection is regarded as the most available treatment of choice, provided the patient’s hepatic function reserved is acceptable for resection [3‐7]. For unresectable huge HCC, TACE is an alternative, but the response rates are generally poor for large tumors [8, 9]. After failure of TACE or patients unsuitable for TACE due to co-existing morbidities such as portal vein thrombosis or other vascular extension, no standard treatment is available, and various clinical trial have been tried, but to date survival benefits have been limited. And without any treatment these patient will not survive more than 3 months [10].

With the recent advancement of radiation therapy technology, Stereotactic body radiotherapy (SBRT) has proven its efficacy in the treatment of liver tumors. In the majority of recent studies, SBRT has been shown to achieve a high rate of local control with low toxicity in particular for small or ≦5 cm tumor [11‐13]. But limited information is available regarding the use of SBRT for treatment of huge unresectable HCC. With the help of internal markers (fiducials) and synchrony tracking of tumor during respiration. SBRT with Cyberknife (Accuray Inc, Sunnyvale, CA, USA) allows more accurate application by reducing the error margin with reducing the amount of normal tissue exposure during treatment, enhancing the chance of treating larger tumor with limited normal liver available or tumor in close proximity to critical organs [14‐17]. Furthermore, fractionated SBRT may have 3 times the biological effect of conventional fractionated radiation therapy [18, 19].

This study retrospectively analyzed the outcomes of 22 patients with unresectable huge HCC with no other treatment options but with good liver function reserve and acceptable performance status treated with Cyberknife (Accuray Inc., Sunnyvale, CA) SBRT. We also attempt to determine survival, toxicity and response after SBRT. And hope these data would provide new hope to these patients who would otherwise be abandoned in terms of therapeutic options.

During the past decade, a number of reports have documented the effect of SBRT on HCC. There remain no optimal dose and fractionation scheme, but the current consensus stated high dose local RT alone or combine with other modalities such as TACE could achieve a high rate of local control [28‐30] However, these reports were mostly limited to smaller tumors or tumor less than 10 cm [31‐36]. For Huge HCC, it remain a challenging role for radiation therapy, because of close proximity to critical organ, limited liver volume available and a relatively poor liver functional status. At present there are only scarce studies on this issue. In our study, our preliminary results support the fact that SBRT could be an alternative treatment for unresectable huge HCC with no other treatment option. 1-yr OS of 50% is comparable to that of TACE for tumor >5 cm [3, 31]. At present, TACE was the most common alternative treatment for inoperable large HCC. Although long-term survival has been reported after TACE, but reported tumor response is achieved in only 17–61% and complete response is rare because of viable tumor cells remain after TACE [8]. After failure of TACE, other treatment options such as target therapy, hepatic intraarterial chemotherapy were unsatisfactory for large HCC. And thus, our present study resulted in a 1-yr. objective response rate of 86.3% (CR, 22.7% and PR, 63.6%). 1-yr. local control rate of 55.56% (Child-Pugh A 66.67%, Child-Pugh B 0%; Radiation dose 40 Gy 71.43%, dose <40 Gy 0%) and a median survival of 11 months (range 2–46 months) were encouraging. Accordingly, we view Cyberknife SBRT as one of the best alternative treatment modality for inoperable huge HCC patient particular for Child-Pugh A patients and those tolerating a radiation dose of at least 40 Gy.

Our present trial was too small to allow stratification by prognostic factors, however, exploratory multivariate analysis showed that a higher radiation dose (40Gy/5 fractions) independently predicted overall survival. Several studies have shown a dose–response relationship between conventional radiation therapy dose and response in HCC. And higher more intense SBRT dose contribute to higher local control rates [32‐36]. Seo et al. [35] prospectively studied 38 patients with inoperable HCC (<10 cm) treated by Cyberknife SBRT, radiation doses range from 33–57 Gy in three to four fractions were prescribed according to tumor volumes. The local response rate was 63% at 3 months after SBRT. And two-year overall survival and local progression-free survival rates were 61.4% and 66.4%., a high radiation dose was found as the independent prognostic factor. While Rusthoven et al. [36], In a phase II study, using 60 Gy in three fractions, resulted in an actuarial in-field local control rate for liver metastasis (< 6 cm) at 1 and 2-yrs after SBRT were 95% and 92%, respectively. Moreover, for maximal diameter of 3 cm or less, 2-yr. Local control rate was 100% and only one case of grade 3 soft tissue toxicity was observed. Hence, high-dose liver SBRT was safe and effective when normal liver tissue constraint was met. Chang et al. [37], recently studied SBRT for colorectal liver metastases in 3 major institutions. The study demonstrates that local control is dose dependent, with a 18-month local control of 84% for total doses ≥ 42 Gy versus 43% for total doses <42 Gy. Overall, the total dose, dose per fraction and biological effective dose were significant in univariate and multivariate analysis. Nevertheless, it must be reminded that most HCC usually associated with liver cirrhosis and poor liver functions was more susceptible to liver toxicity rather than liver metastasis. In our present study, we strictly specified that a minimum volume of 700 cc of normal liver should receive a total dose less than 15 Gy.

Compared with other Radiation therapy technique, Cyberknife SBRT with respiratory synchrony tracking system demonstrated its advantage in treating huge HCC with a limited normal liver preserved. These systems are demonstrably more conformal and able to minimize radiation outside the PTV, thus sparing critical structures near the tumor than those generated by other system. This also delivered higher biological effective doses without increasing incidence of liver toxicity incidences, and attained a higher local control rate.

In our present study, other than transient hepatic function disorders and gastrointestinal toxicities commonly observed. Neither grade 3 complications nor radiation-induced liver disease (RILD) were observed. There were 5 patient suffered from Grade 1–2 painful musculoskeletal complication, notably right lower rib pain and skin induration, all these patients have huge HCC closely adherent to adjacent ribs and skin. In order not to compromise the PTV coverage, rib and skin constraints were not considered, but fortunately, no severe complication above grade 2 was observed. Although musculoskeletal complications were not life-threatening event,these morbidity should be considered in treating huge HCC with high SBRT dose. In the recent multicenter analysis by Benedict et al. [24] reported SBRT doses in 5 fractions, the maximum point dose of 43 Gy (8 Gy/fx) on rib volume should be less than 1 cc. And less than 10 cc of skin volume should not receive more than a max point dose of 39.5 Gy (7.9 Gy/fx). In another study by Dunlap et al. [38], recommended Chest wall volume receiving 30 Gy in three or five fractions should be limited to <30 cc. to reduce toxicity without compromising tumor coverage.

Huge HCC have shown to harbor microvessel tumor invasion, poor differentiation, a propensity for multinodular lesions and subsequent recurrence. A Recurrence rate of more than 70% after resection of very large HCC (>10 cm) was reported by Shah et al. [8]. In our study, regional and local recurrences remain the major pattern of failure. Thus, combining SBRT with other treatment modality with non-overlapping toxicity such as TACE, target therapy, and other potential drugs with anititumor effects on HCC in clinical studies may potentially increases local control, decrease regional failure and prolonged survival rates.

The major limitation of this study is that it was a retrospective single-institution study with small sample size, the median survival rate was only 11 months, which is most likely related to the unfavorable prognostic features of the patient enrolled. Furthermore, late toxicity may be underestimated as a result of limited survival, especially when the higher than conventional fractional dose is considered.

In conclusion, despite its unfavorable prognosis, our study supports that Cyberknife SBRT is feasible in treating huge unresectable HCC, tumor response rate of 86.3% (CR + PR), 1-yr. local control rate of 55.56%. And the 1-yr. Overall survival rate of 50% were encouraging. While patients with a score of Child-Pugh A and those receiving doses of at least 40 Gy were able to achieved a 1-yr local control rate of 66.67% as well as 71.43% were promising Acute toxicities were mild and tolerable. However, local and regional recurrence remained the major problem. Prospective studies of combination of SBRT with other treatment modalities may be suggested.